The present invention relates to novel mitomycin derivatives showing antibacterial and anti-tumor activities, a process for production thereof and an anti-tumor composition containing the same.
Mitomycins are generally known as antibiotics showing antibacterial and anti-tumor activities. Representative mitomycins include mitomycin A, mitomycin B, mitomycin C and porfiromycin, which are described in Merck Index, 10th edition; mitomycin D and mitomycin E, which are described in Japanese Published Unexamined Patent Application No. 122797/79; mitomycin F, which is described in Japanese Published Unexamined Patent Application No. 45322/80; etc. These mitomycins can be isolated from culture liquor of Streptomyces caespitosus. Further, 9-epi-mitomycin B and 9-epi-mitomycin D are chemically derived from mitomycin B (U.S. Pat. No. 4,395,558). Recently, the absolute configuration of mitomycin has been corrected [J. Am. Chem. Soc., 105, 7199 (1983)]. Structures of various mitomycins mentioned above corrected according thereto are shown by formulae A and B (the same shall apply to formula C).
______________________________________ Formula A: Main mitomycins obtained from natural source ##STR3## Mitomycin X.sub.A Y.sub.A Z.sub.A C-9 ______________________________________ A OCH.sub.3 CH.sub.3 H .beta. B OCH.sub.3 H CH.sub.3 .alpha. C NH.sub.2 CH.sub.3 H .beta. D NH.sub.2 H CH.sub.3 .alpha. E NH.sub.2 CH.sub.3 CH.sub.3 .alpha. F OCH.sub.3 CH.sub.3 CH.sub.3 .beta. J OCH.sub.3 CH.sub.3 CH.sub.3 .alpha. Porfiromycin NH.sub.2 CH.sub.3 CH.sub.3 .beta. ______________________________________ Formula B: 9.beta.-Mitomycins having hydroxy group at the 9a-position ##STR4## 9-epi-mitomycin B X.sub.B = OCH.sub.3 9-epi-mitomycin D X.sub.B = NH.sub.2 ______________________________________
In addition, mitomycins having a double bond at the 9- and 10-positions are also known. Processes for producing them are disclosed in EP 0008021A1. The structure of a double bond type mitomycin is shown by formula C.
______________________________________ Formula C: Double bond type mitomycin ##STR5## X.sub.C Y.sub.C Z.sub.C ______________________________________ Mitomycin H OCH.sub.3 H CH.sub.3 Mitomycin G NH.sub.2 CH.sub.3 CH.sub.3 Mitomycin K OCH.sub.3 CH.sub.3 CH.sub.3 9a-ODemethylmitomycin G NH.sub.2 H CH.sub.3 1a-Demethylmitomycin G NH.sub.2 CH.sub.3 H 1a-Demethylmitomycin K OCH.sub.3 CH.sub.3 H ______________________________________
Mitomycins exhibit excellent anti-tumor activity, but they cause side effects such as decrease of leucocytes, etc. on the other hand. Therefore, for the purpose of increasing the activity or reducing the toxicity, a large number of derivatives have been synthesized and their biological properties have been investigated.
Among these mitomycin derivatives, examples of compounds containing a modified amino group at the 7-position, which are relevant to the present invention, include those reported in J. Med. Chem., 24, 975 (1981), J. Med. Chem., 26, 16 (1983), J. Med. Chem., 26, 1453 (1983), J. Med. Chem., 27, 701 (1984), etc. It is also reported in these publications that mitomycin derivatives having a modified amino group at the 7-position exhibit an anti-tumor activity in vivo. Among the mitomycin derivatives having a modified amino group at the 7-position, examples of compounds which are especially relevant to the present invention are disclosed in GB 2121796A. It is reported that inter alia, 7-(dimethylaminomethylene)amino-9a-methoxymitosane (hereinafter referred to as Compound A) disclosed in Example 8 of the patent application possesses a particularly excellent anti-tumor activity. However, the compounds of the patent application are obtained using as starting materials mitomycin A, mitomycin C, porfiromycin and 7-N-methylmitomycin C and thus limited to compounds that have the same configuration as that of mitomycin C (cf. GB 2121796A).
On the other hand, the mitomycin derivatives having an anti-tumor activity which are covered by the present invention are shown by the following formulae (I-1), (I-2) and (I-3): ##STR6## wherein R.sub.1 and R.sub.2 represent a hydrogen atom or a lower alkyl group; Y and Z represent a hydrogen atom or a methyl group; and represents .alpha.- or .beta.-bond, provided that Y represents a hydrogen atom when the substituent at the 9-position takes .beta.-configuration.
The compound shown by formula (I-1) [hereinafter referred to as Compound (I-1); and compounds of other formula numbers are likewise referred to] is synthesized using mitomycin B or its analogues as starting compounds when the substituent at the 9-position take .alpha.-configuration. Examples of the analogues include mitomycin D and mitomycin E which have an amino group at the 7-position. These derivatives are obtained from nature as extremely minor components in the fermentation of mitomycin C (Japanese Published Unexamined Patent Application No. 122797/79), and are difficult to obtain unless they are chemically derived from mitomycin B.
Mitomycin B is also a compound isolated as a minor component in the fermentation of mitomycin C and, it has thus been considered to be difficult to obtain an amount usable as a starting compound in chemical synthesis. However, co-researchers of the present inventors have investigated in detail culture conditions for the fermentation of mitomycin C and a method for isolation and purification of mitomycin B with an attempt to produce an improved amount of mitomycin B and succeeded in greatly improving productivity of mitomycin B. As a result, it has become possible to produce mitomycin B in large amounts at a low cost. Thus, the present invention which utilizes mitomycin B as a starting compound has come to be of industrial value.
On the other hand, the compounds whose substituent at the 9-position takes .beta.-configuration belong to generally well known mitomycins. A representative is mitomycin C. However, all the mitomycins obtained from nature whose substituent at the 9-position takes .beta.-configuration have a methoxy group at the 9a-position. Mitomycins having the same configuration as that of mitomycin C, namely, taking 9-.beta. configuration and having 9a-OH (cf. formula A) are generally difficult to obtain. 9-Epi-mitomycin D relevant to the present invention is a special compound that can be obtained using mitomycin B as a starting compound. Thus, the compounds which are covered by the present invention are extremely characteristic in chemical structure and are hardly obtainable even to one skilled in the art, although they may be collectively referred to as mitomycins. Such a background is also the case with the double bond type mitomycin [Compound (I-3)]. In addition, it has been proved by experiments that some compounds of the present invention exhibit superior anti-tumor activity against leukemia P-388 to Compound A (shown in Reference Example) described in GB 2121796A (later described). The present invention is thus obviously characteristic as compared to the prior art.
As is evident from the publications referred to hereinabove, a large number of mitomycin derivatives have already been synthesized, but development of more excellent anti-tumor agents has still been desired in view of enhancement of anti-tumor activity or reduction of toxicity. During the course of extensive investigations for purposes of producing substances having such properties, the present inventors have also synthesized Compound A independently from GB 2121796A, and noted its excellent anti-tumor activity. As a result of further investigations on production of mitomycin derivatives having a more excellent antibacterial activity and anti-tumor activity with reduced toxicity, the present inventors have found the compounds having biochemical properties superior to those of Compound A and have accomplished the present invention.